DESCRIPTION: The overall goal of our current research is to develop novel treatments and drug delivery methodologies for presently untreatable, socially significant conditions involving CNS and meninges, such as meningeal and brain cancer, neurodegenerative diseases, trauma, infections and enzyme deficiencies. Hypothetically, the initial bolus translocation in the CSF is hydrostatically controlled, and the subsequent solute transport in the cerebrospinal fluid (CSF) is governed by active biomechanical remixing (and not by directional flows or diffusion). Solutes are thus delivered to entrances of liquid conduits enveloping the arteries and veins leading into the CNS (Virchow-Robin spaces). The periarterial conduits are rapidly remixed along the arterial axes due to the pulsation of the arteries. The data clearly shows that the boundaries of the periarterial conduits are penetrable for solutes, including large molecules. Thus, solutes administered to the CSF have direct access to all compartments of CNS parenchyma. The final outcome of the leptomeningeal drug transport will depend on the solute (e.g., drug) behavior in each of the above transport processes, none of which has been studied systematically. The effects of physiological factors on drug transport in the CSF may depend on the presence of pathologies, such as inflammation and tumors. Optimization of a drug molecule or a drug delivery system for certain behavior in each of the transport processes is expected to enable preferential routing to a desirable subcompartment of either CNS or meninges. However, lack of quantitative mechanistic knowledge on the hydrostatic and hydrodynamic solute translocation in the CSF hinder the development of novel drugs optimized for delivery through the CSF. The objectives of the proposed work are (a) to investigate the mechanisms of hydrostatic bolus translocation and the subsequent hydrodynamically driven solute transport, and (b) to compose and test a mechanistic pharmacokinetic model suitable for drug development. The studies will be carried out in rodents and in non-human primates. Impact. The study will result in new physiological knowledge and novel approaches facilitating drug development for presently untreatable conditions involving CNS and meninges.